al analysis of small G protein Ral in pancreatic carcinogenesis and acquisition of invasive potential

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K08791
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 55020:Digestive surgery-related
• Research Institution: Tohoku University
• Principal Investigator: Ohtsuka Hideo 東北大学, 医学系研究科, 非常勤講師 (50451563)
• Co-Investigator(Kenkyū-buntansha): 堀内 久徳 東北大学, 加齢医学研究所, 非常勤講師 (90291426) ; 石田 晶玄 東北大学, 大学病院, 講師 (90619660)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: 膵癌 / ATM / Ral

Outline of Final Research Achievements

Ral (Ras like) GTPase (Ral) is a member of the Ras family and is activated downstream of Ras. Since Ras is regarded as a driver gene in pancreatic cancer, Ral, downstream of Ras, is important for its malignancy.
Ral is deeply involved in the repair mechanism (DDR) of DNA damage caused by radiation. We focused on the DDR mechanism of DNA damage, especially the Ataxia telangiectasia mutated (ATM) molecule, and investigated its role in pancreatic cancer and its relationship with Ral. We found that ATM knockdown is involved in the acquisition of invasive and metastatic potential, and that ATM is associated with decreased sensitivity to anticancer drugs and shorter postoperative survival.

Free Research Field

消化器外科学

Academic Significance and Societal Importance of the Research Achievements

ATMは、膵癌で変異頻度の高いDDR遺伝子の１つとされており、2-18％に体細胞変異が、1-34％に生殖細胞変異が報告されている．本研究では、膵癌臨床検体におけるATMおよび活性化体リン酸化ATM の発現を検討し、リン酸化ATMの発現が低い症例で生存期間が有意に短く、治療成績が不良であることを明らかにした。また、培養膵癌細胞を用いて、RNA Sequencing 法により ATM下流域の遺伝子の発現変化を検討、抗がん剤感受性に深く関与することを明らかにした．ATMとその下流域での分子生物学的メカニズムの解析は、特にその変異陽性症例での新たな治療ターゲットの開発を可能にすると考えられる．